Epstein-Barr virus (EBV) is a ubiquitous human herpes virus, which causes both infectious mononucleosis and lymphoproliferative diseases. The oncogenic development of other cancers (e.g. nasopharyngeal carcinoma and a subgroup of EBV-positive gastric cancer) is also associated with the latent infection of EBV virus. EBV's life cycle processes, like viral DNA replication and segregation, a viral protein, Epstein-Barr nuclear antigen 1 (EBNA1) is critical. Considering the indispensable homodimerization criteria for EBNA1 to function properly, specifically blocking the dimer formation presents a way to treat latently EBV-infected tumor. Recently, several of EBNA1 specific inhibitors have been reported. A small molecule named Eik1 has been developed through high-throughput screening to target the EBNA1 amino acid sequence 459-607 of the dimerization domain, while some peptide-based inhibitors have been reported to similarly work in the region of 560-574. However, the lack of specific subcellular localization and no responsive binding limit these existing EBNA1 inhibitors' effectiveness on imaging and inhibition of EBNA1 dimerization, furthermore hindering the efficacy of selective inhibition of cancer cells with EBV latent infection.
Literature reveals that EBNA1 is broadly distributed in the nucleus of EBV-infected cells. The process of EBNA1 tethering to host cell chromosomes is critical to efficient replication of EBV-derived plasmids. The development of responsive target-specific bioprobes for in vitro microscopic studies of EBNA1 at the nucleus is still rare. Accordingly, it is an objective of the present invention to provide nucleus permeable and EBNA1-specific molecules.
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